Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the United States (Jemal et al, 2003), and over 30% of these patients are expected to die of their malignancy. Squamous cell carcinoma accounts for more than 90% of head and neck cancer cases. Although metastatic disease at the time of diagnosis is rather uncommon, and despite aggressive use of up-front concurrent radiation and cisplatin-based chemotherapy, approximately 20% of the patients will develop metastases. Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis. Their median survival is about 6-8 months. Selected patients with locally recurrent disease can be treated with a curative intent with locoregional therapies, such as salvage surgery or radiation (De Crevoisier et al, 1998); however the majority of these patients die of their disease. Despite high response rates, combination chemotherapy has not been shown to produce a survival benefit compared to single agents in randomized trials in patients with recurrent/metastatic head and neck cancer (Forastiere et al, 1992; Jacobs et al, 1992; Clavel et al, 1994). A phase III randomized study conducted by SWOG compared cisplatin-based combination chemotherapy to single agent methotrexate (Forastiere et al, 1992). The objective response rates were 32%, 21%, and 10%, for cisplatin/5-Fluorouracil (5-FU), carboplatin/5-FU, and single methotrexate, respectively, but the median overall survival was not statistically different between the three arms (ranged between 5 to 6.6 months). Moreover, toxicity was increased with combination therapy, especially with the cisplatin-based regimen. Another randomized study conducted in the US demonstrated a significantly higher response rate of 32% for the combination of cisplatin and 5-FU versus 17% and 13% for single agent cisplatin and 5-FU, respectively (Jacobs et al, 1992). However, the median survival of all patients was 5.7 months, with no difference between the three arms. Hematologic toxicity was increased in the combination arm.